Cyclized o-carboxybenzenesulfonic acid derivatives and method of preparing the same



United States Patent 3,284,450 CYCLIZED o-CARBOXYBENZENESULFONIC ACID DERIVATIVES AND METHOD OF PREPARING THE SAME Adriaan Kraaijeveld, Oegstgeest, and Antony M. Akkerman, Amsterdam, Netherlands, assignors to N.V. Nederlandsche Comhinatie voor Chemische Industrie, Amsterdam, Netherlands, a limited-liability company of the Netherlands No Drawing. Filed Sept. 16, 1963, Ser. No. 309,595 Claims priority, application Netherlands, Sept. 21, 1962,

283,525 7 Claims. (Cl. 260-243) This invention relates to new cyclized o-car-boxybenzenesulfonic acid derivatives and to a method of preparing the same.

A large number of diuretically active sulfamoyl derivatives of saccharin, partly represented by the formula:

are described and claimed in U.S. Patent 2,957,883. In said patent the meaning of R is defined as selected from the group consisting of hydrogen, a lower alkyl radical, a lower alkenyl radical, a phenyl-lower alkyl radical, a lower alkanoyl radical, a phenyl-lower alkanoyl radical, an omega-halo-lower alkyl radical, an omega-hydroxylower alkyl radical, an omega-(mono-lower-alkylamino)- lower alkyl radical, an omega-(di-lower alkylamino)-lower alkyl radical, an omega-piperidyl-lower alkyl radical, an omega-pyrrolidyl-lower alkyl radical, an omega-morpholinyl-lower alkyl radical, an omega-carboxy-lower alkyl radical, an omega carbalkoxy-lower alkyl radical, an omega-carboxy-lower alkanoyl radical, and an omegacarbalkoxy-lower alkanoyl radical.

From the many well-defined meanings given for R one might conclude that this enumeration is limitative with regard to the diuretic properties of sulfamoyl derivatives of the type disclosed.

However, it has been found that compounds represented by the formula:

N-CHz-CO-R having substituents in the benzene nucleus, are described by Kyuji Abe. Thus, N-phenacyl-saccharin is disclosed in Japanese patent 9681 (1958) (compare CA. 54, 5575 e (1960)), whereas a-benzoylethyl-saccharin is mentioned in J. Pharm. Soc. Japan, 76, 1058 (1956).

In addition to the foregoing it has been found that the saccharin derivatives according to the invention can be converted by way of simple reactions in compounds represented by the formula:

in which R and X have the above-defined meanings, and R is a hydrogen atom or an alkyl, alkenyl, alkynyl, aralkyl or a keto-substituted alkyl or aralkyl radical, containing up to 9 carbon atoms. These compounds too are new, and they show pharmacological effects similar to those of the starting materials represented by Formula II. It has been found that, on the whole, the activity of the derivatives containing a six-membered ring is stronger than that of the five-membered saccharins. The compounds of the invention are of particular interest because of their low toxicity.

The new derivatives can be prepared by methods known per se for analogous compounds. Particularly suitable is the method comprising condensation of saccharin derivatives of the formula NH X 02 IV with a reactive ester of an alcohol HOCH COR, R and X having the above-defined meanings.

The saccharin derivatives thus obtained can be converted into the benzothiazinones of the Formula III on the analogy of a method reported by Kyuji Abe et al., J. Pharm. Soc. Japan, 76, 1058 (1956).

In this method the saccharin derivative is heated in alcohol with an excess of sodium alcoholate, whereupon the benzothiazinone formed is isolated. However, it has been found that it may be useful to perform the reaction in anhydrous solvents other than alcohol, such as dimethylformamide or pyridine. By doing so the yields tend to be increased, whereas purer products may be obtained.

If desired, the substituent R can be introduced afterwards by usual methods.

Some of the compounds according to the present invention have been administered to test-animals, in order to determine the influence on the electrolyte and water excretion in the urine. At the same time the influence on the pH of the urine was examined. The results obtained are listed in Tables I and II; the values stated therein represent the mean differences in excretion between treated and control animals under the screening conditions. The electrolyte excretion is given in milliequivalents and the water excretion in milliliters both per kilogram body-weight of the tested animals.

In the last column the extent of rise or fall in the pH of the excreted urine is stated.

In order to compare the diuretic properties with those of a prior art compound, the same features are determined after the administration of an equal dose of chlorothiazide, a well known diuretic of the benzothiadiazine type. The following values have been found in this compound under the screening conditions for Na, K, Cl, H and pH, respectively: 1.4, 0.1, 1.6, 8, and 0.4.

The effects of the new compounds on blood pressure have been examined on experimentally hypertensive rats (Goldblatt rats). Hereby blood pressure is measured by the tail-plethysmometric method as described in Acta Phys. Pharm. Neerl. 3, 472 (1954).

Significant effects (i.e. a decrease in blood pressure of at least 10 mm. of mercury) have been observed in the compounds 2, 3, 4, 5, 7 and 8 of Table I and in the compounds 7, 9, 16, 17, 19 and 20 of Table II at an oral dosage of 40 mg./kg.

The following examples, which describe more exactly the preparation of some of the new compounds according to the invention, are only illustrative for the methods which can be used, and are not intended to limit the invention to the particular methods or compounds given.

With regard to the tables, it should be remarked that the derivatives mentioned therein are not stated for the purpose of limiting the invention either, but only to show the useful properties of compounds within the scope of the general formula.

EXAMPLE 1 2-phenacyl-5-chl0r0-6-sulfamoyl-saccharin To a solution of 8 grams of -chloro-6-sulfamoyl-saccharin in 50 ml. of dimethylformamide are added 1.3 grams of a 50% suspension of sodium hydride in mineral oil. After completion of the reaction (the grains of sodium hydride then have disappeared and efiervescence has ended), 5.4 grams of phenacyl bromide are added and the mixture is stirred for one hour at a temperature of 130 C. After cooling, the reaction mixture is poured into 250 ml. of water with stirring. The 5-chloro-6-sulfamoyI-Z-phenacyI-saccharin precipitated is crystallized from dimethylformamide. Melting point 251252 C.

EXAMPLE 2 Z-(p-bromophenacyl) -5-chloro-6-sulfamoyl-saccharin In the same way as described in Example 1, however substituting p-bromophenacyl bromide for phenacyl bromide, Z-(p-bromophenacyl)-5-chloro-6-sulfamoyl-saccharim is obtained. Melting point 269-270 C.

EXAMPLE 3 2-(2-0x0-2-cycl0pentyl-ethyl) -5-c/1l0r0-6-sulfam0ylsaccharin A solution of 35.5 grams of 5-chloro-6-sulfamoyl-saccharin in 100 ml. of dimethylformamide is transformed into a solution of the monosodium salt of said saccharin with the aid of a 50% suspension of sodium hydride in mineral oil. Hereupon 17.6 grams of cyclopentylchloromethyl ketone are added and the mixture is heated for one hour between 120 and 130 C. After cooling, the mixture is poured into water and the precipitate formed is washed with water, dried, washed with petroleum ether and dried again. The 2-(2-oxo-2-cyclopentyl-ethyl)-5- chloro-6-sulfamoyl-saccharin obtained, is crystallized from acetic acid. Melting point 248249 C.

EXAMPLE 4 3-benzoyl-6-chl0r0-7-sulfamoyl-3,4-dihydr0-1,2-

benz0thiazilz-4-0ne-1 ,1 -di0xide To a warm solution of 0.6 gram of sodium methylate in 4 ml. of absolute alcohol, 1.5 grams of 2-phenacyl-5- chloro-6-sulfamoyl-saccharin are added. The mixture is heated at 60 C. for 3 minutes and thereupon cooled to room temperature.

The deep-red solution is acidified with dilute hydrochloric acid till the color changes into yellow. By adding water to the mixture, the 3-benzoyl-6-chloro-7-sulfamoyl- 3,4 dihydro 1,2-benzothiazin-4-one-1,l-dioxide formed precipitates. The compound is crystallized from n-butanol. Melting point 264 C.

EXAMPLE 5 3-cyclopentylcarb0nyl-6-chl0r0-7-sulfam0yl-3,4-dihydr0- 1 ,2-benz0lhiazin-4-0ne-1,1-di0xide A warm solution of 5.4 grams of sodium methylate in 40 ml. of absolute alcohol is poured onto 8.1v grams of 2 (2 oxo 2 cyclopentyl ethyl) 5 chloro 6 sulfamoyl-saccharin, whereupon the mixture is heated to 60 C. for 3 minutes. After cooling, the solution is acidified by which the color changes from red to yellow. By pouring the mixture into water, a precipitate appears consisting of 3 cyclopentylcarbonyl-6-chloro-7-sulfamoyl-3,4-dihydro-1,2-benzothiazin-4-one-1,l-dioxide. The compound is crystallized from aqueous methanol. Melting point 221- 223 C.

EXAMPLE 6 3 trimethylacetyl -6-ch l0r0-7-sul fam0yl-3 ,4 -d ihydro- 1,2-benz0thiazin-4-one-1,I -di0xide To a solution of 1.0 gram of 2-(2-oxo-3,'3-dimethylbutyl)-5-chloro-6-sulfamoyl-saccharin in 5 ml. of dimethylformamide is added with stirring 0.5 gram of sodium methylate. The temperature of the mixture increases and the mixture becomes dark in color. After some 15 minutes the mixture is poured into 50 ml, of water to which 3 ml. of 4 N hydrochloric acid had been added before. The yellow precipitate is crystallized from aqueous methanol, yielding pure 3-(trimethylacetyl)-6-chloro-7-sulfamoyl 3,4 dihydro 1,2 benzothiazin 4 one 1,1- dioxide melting at 262 C.

EXAMPLE 7 2-methyl-3-cycl0pentylcarb0nyl-6-chl0r0-7-sulfam0yl-3,4- dihydro-1,2-benzothiazin-4-one-1,I-dioxide To a solution of 2.1 grams of 3-cyclopentylcarbonyl-6- chloro 7 sulfamoyl 3,4 dihydro 1,2 benzothiazin- 4-one-1 ,l-dioxide in 4 ml. of dimethylformamide are added 0.24 gram of a 50% suspension of sodium hydride in mineral oil. When the evolution of hydrogen has ended, 2 ml. of methyl iodide are added, whereupon the mixture is heated to about 35 C. for one hour.

The reaction mixture is poured into cold water and the precipitate consisting of 2-methyl-3-cyclopentylcarbonyl- 6 chloro 7 sulfamoyl 3,4 dihydro 1,2 benzothiazin-4-one-1,1-dioxide recrystallized from aqueous methanol.

Melting point 214216 C.

EXAMPLE 8 Z-benzyl-3-acetyl-6-chl0r0-7-sulfamoyl-3,4-dilzydr0-1,2-

benzothiazin-4-0ne-1 ,1 -di0xide Into a mixture of 20 ml. of water and 2 ml. of l N aqueous sodium hydroxide, 0.70 gram of 3-acetyl-6-chloro- 7-sulfamoyl-3,4-dihydro-1,2-benzothiazin-4-one 1,1 dioxide are dissolved, whereupon 0.25 ml. of benzyl chloride are added. The mixture is heated with stirring to 60 C. for 2 hours. After cooling, the solution is acidified with dilute hydrochloric acid. The precipitate formed is filtered off and recrystallized from a mixture of acetone and petroleum ether yielding pure 2-benzyl-3-acetyl-6- chloro-7-sulfarnoyl-3,4-dihydro-1,2-benzothiazin-4-one 1, l-dioxide.

Melting point 242-243 C.

EXAMPLE 9 2-methyl-3-propionyl-6-chloro7-sulfam0yl-3,4-dihydr0- 1 ,2 benzozhiazin-4 one-] ,1 dioxid e In the same Way as described in Example 7, however, substituting 3propionyl-6-chloro-7sulfamoyl-B,4-dihydro- 1,2-benzothiazin-4-one-1,l-dioxide for the 3-cyclopentylcarbonyl derivative, 2-methyl-3propionyl-6-chloro-7sulfamoyl-3,4-dihydr-1,2-benzothiaZin-4-one-1,1 dioxide is obtained.

Melting point 162-165 C.

In the same way as described in Example 1, however, substituting 2-0xopr0pyl bromide for phenacyl bromide, crude 2(2-oxopropyl)-5chloro-6-sulfarnoyl-saccharin is obtained. The compound is crystallized from a mixture of acetone and petroleum ether.

Melting point 246-248 C.

EXAMPLE 1 1 2- (2-oxoheptyl 5-ch loro-6-sulfam0yl-saccharin In the same way as described in Example 1, however, substituting 2-oxoheptyl chloride fior phenacyl bromide, 2- (2-oxohe-ptyl)5-chl0r0-6asulfamoyl-saccharin is obtained.

The crude compound is recrystallized from ethanol.

6 Melting point 203-207 C.

EXAMPLE l2 In the same way as described in Example 4, however, substituting 2-(2-oxo-3-methyl-butyl) 5 chlono 6 sulfamoyl-saccharin for the 2-phenacy1 derivative, 3-isopropylcarbonyl-6-chlono-7-sulfamoyl-3,4 di-hydro 1,2- benzothiazin-4-one-1,1-dioxide is obtained which is recrystallized from methanol.

Melting point 256-259 C.

EXAMPLE 13 2-methyl-3 isopropylcarbonyl-6 ch l0r0-7-sul fam0yl-3 ,4 dihydro-I,2-benz0thiazin-4-0ne-1,1dioxide TABLE I The influence of substituted saccharin derivatives according to Formula II on the electrolyte and water excretion and on the pH of the urine by rats, after the oral administration of 15 mug/kg.

Place and kind of the substituents Effects measured Compound tested R 5 6 Na. K C1 H2O pH 1 C H Cl 802N112" 0.8 0. 4 1.0 6 0 2 Br c1 sommo. 4 o. a o. e 2 0. 4

8 CgHi C1 802N112- 1. 5 0. 1 1. 6 7 O. 1

O 4 /CH; 01 N112" 0.2 0. 0 0.0 2 0.0

CH; Cl SOzNHz. 3. 0 0. 2 3. 1 17 O. 1 C3H1 C1 S 02NH2- 2. O 0. 0 2. 1 10 0. 1 CH Cl H 0. 4 0. 0 O. 3 -2 0.1 C4H9 Cl SOzNI-h- 2. 1 0. 4 2. 7 12 0. l CsHu C1 SO2NHz-. 2. 5 0. 1 2.8 14 O.! CHQPCaHi c1 SOZNHZQ 0. s 0.6 1.1 10 0. 2

CHz-O 01 SO2NHz.- 0.1 o. 4 o. 3 3 0. 2

--CI-I2C H Cl SOzNH2- 1. 2 0.0 1. 5 7 0.1 CH(CHa)a C1 SO NH2 1.2 O. 1 1. 4 3 0. 2

- Cl SO2NH2- 2. 1 0. 3 2. 5 12 0. 0

C(CH3)3 Cl S02NI'I2 2.0 0.2 2.1 12 O. 2

TABLE 11 The influence of substituted benzothiazine derivatives according to Formula III on the electrolyte and water excretion and on the pH of the urihe by rats, after the oral administration of 15 mg./ kg.

Eilects measured Compound tested 2 R= 7 Na K 01 E20 pH 1 CH5 c1 501N112- 4.3 0.9 4. s 23 o 2 Br o1 502N111" 3. 2 0. 4 3. 0 0. 5

3 CH3 Q-Br c1 302N112 3. 3 0.5 4 13 0.1

4 C2H5 c1 302N112" 1. 7 0. 4 1. 0 3 --0. 3 5 CH1 C2H5 C1 301N112 0. 5 1.3 0. 2 33 1. 3

CH: 3 o1 801N112" 0.5 0.2 0. 5 1 0. 1

01 s02NH1.. 0. 4 0. 2 0. 2 1 0 01 SOZNHL 0. 5 0. 2 0. 7 3 0. 1

01 SOzNH1 1. 2 0. 3 1. 3 7 0 c1 SOzNH-z- 3. 9 0. 3 3.3 14 1. 0 01 301N111 3. 9 0. 0 3. 3 21 1. 2 c1 302N111" 3.1 1. 0 2. 5 13 1. 3 01 SOzNHz- 0. 4 0.3 0. 2 2 0. 3 c1 301N112. 0. 2 0. 2 0.0 1 0. 3 CHy-C=C c1 302N111 0.3 0.1 0. 5 3 0.1 CH2COCH3 CH3 Cl sOZNII2 0.1 0.0 0.1 1 0.1 011-15 01 301N112. 5. 0 0. 3 4. s 23 1. 2 *c1111 01 S02NH2. 3. 3 0. 7 4. 3 17 0.1 05111 01 301N112. 0. 3 1. 7 0. 0 3s 1. 4

C4H9 Cl SOzNHz- 4. 7 0. 8 5. 4 26 0 C1H1 c1 301N111. 4.1 1. 4 2. 7 23 1. 3 C5H11 Cl SO2NH2 3.4 0.4 3.4 17 0. 1 C5H11 01 3013111.. 2. 3 0. 3 1. 5 11 2. 2 CeHn Cl SOzNHz- 0. 8 0. 2 0. 8 3 0. 7 c1H11 c1 S02NH2 1. 6 0. 2 1. 5 3 0. 4 O3H17 Cl SO2NH2" 1.4 0.2 1.5 8 0.1 C3H17 Cl SO2NH2- 2. 1 0. 4 2. 1 16 0. 6 -(CH2)2CsH5 01 501N111. 4.1 0. 5 4. 7 25 0.1

Gm-Q c1 802N112" 0. 3 0.2 0. 4 4 0. 2

CH2C5H5 Cl SOzNHz- 3. 3 0. 4 3. 6 21 0. 1 CHz)2C3Hs Cl SOzNHn- 1. 7 0. 3 2. 0 12 0. 1

-03; c1 I-I. 0. 4 0.1 -0.2 0 0 -CH3 (:1 11 0. 7 0.1 0. 3 4 0. 3

CH3 CHz-Q 01 801N112- 2. 2 0. 5 1. 2 11 1. 3

36 CH3 CH2CGH5 Cl 802N111" 2. 5 0. 8 2 1 19 1.2

33 CH(CH1)1 c1 SO2NHz 1. 9 0.3 2. 0 12 0.2 39 CH3 CH(CH3)2 Cl 302N111 5. s 0. 9 5.1 33 1. 3

41 c111 Cl 801N" 1.3 0.1 1. 3 0 0. 2

42 C(0H1 1 C1 302N111. 2.1 0. 5 2. 3 1e 0. 2 43 CH3 cwHm c1 802N112" 4. 2 0. 3 4. 7 19 0. 7

We claim: 1. A compound having the formula:

NCH2C O-R in which:

X is selected from the class consisting of hydrogen and the sulfamoyl group, and R is selected from the class consisting of alkyl having up to three carbon atoms, biphenylyl, phenyl substituted by halogen having a maximum atomic weight of 80, and 1,3-benzodioxole.

2. Compounds having the formula:

on N-R1 s X 03 in which:

X is selected from the class consisting of hydrogen and the sulfavmoyl group;

R is selected from the class consisting of alkyl having up to 12 carbon atoms, phenyl-lower-alkyl, phenyl, biphenylyl, p-henyl subsituted by halogen having a maximum atomic weight of 80, :phenyl substituted by a maximum of two aliphatic ether functions in which a maximum of 2 carbon atoms are involved, and rcycloalkyl and cycloalkyl-alkyl containing up to 8 carbon atoms; and

R is selected from the class consisting of hydrogen, and alkyl, alkenyl, alkynyl, aralkyl, and keto-substit-uted alkyl and aralkyl radicals, containing up to 9 carbon atoms.

3. 2-(2-ox'op'ropyl)-5-chloro-6-sulfamoy1-saccha1rin.

4. 2 methyl 3 propionyl 6 chloro 7 sulfamoyl- 3,4-dihydro-1,2-benzothiazin-4-one-1,1-dioxide.

5. 2 methyl 3 isopropylcarbonyl 6 chloro 7- sulfamoyl 3,4 dihydro 1,2 benzothiazin 4 one- 1,1-dioxide.

6. A method of preparing substituted sacoharins having the formula:

in which:

X is selected from the class consisting of hydrogen and the sulfamoyl group, and R is selected from the class consisting of alkyl having up to 12 carbon atoms, phenyl-l ower-alkyl, phenyl, biphenylyl, phenyl subsituted by halogen having a maximum atomic weight of 80, phenyl subsituted by a maximum of two aliphatic ether functions in which a maximum of 2 carbon atoms are involved, and cycloalkyl and cycloalkyl-alkyl containing up to 8 carbon atoms, comprising the steps of reacting a chloro-saccharin selected from the class consisting of unsubstituted and sulfamoyl substituted chlorosaccharin with a reactive ester of an alcohol of the formula HOCH CO-R, in which R has the above defined meaning, in the presence of a condensing agent. 7. In a method of preparing compounds according to the formula u Cl C (IJHCOR NR1 in which:

X is selected from the class consisting of hydrogen and sulfamoyl,

011-0 OR 11m X 02 with a reactive ester of an alcohol of the formula R OH.

References Cited by the Examiner UNITED STATES PATENTS 2,776,281 1/ 1957 Wright 260-243 2,957,883 10/1960 Novello 260-301 3,050,553 8/ 1962 Novel-lo 260301 OTHER REFERENCES Abe et .al.: J. Pharm. Soc. Japan, volume 76 (1956), pages 1058-63.

WALTER A. MODANCE, Primary Examiner.

J. M. FORD, Assistant Examiner. 

1. A COMPOUND HAVING THE FORMULA: 1,1,3-TRI(O=),2-(R-CO-CH2-),X,CL-2,3-DIHYDRO-1,2IN WHICH: X IS SELECTED FROM THE CLASS CONSISTING OF HYDROGEN AND THE SULFAMOYL GROUP, AND R IS SELECTED FROM THE CLASS CONSISTING OF ALKYL HAVING UP TO THREE CARBON ATOMS, BIPHENYL, PHENYL SUBSTITUTED BY HALOGEN HAVING A MAXIMUM ATOMIC WEIGHT OF 80, AND 1,3-BENZODIOXOLE.
 2. COMPOUNDS HAVING THE FORMULA: 1,1,4-TRI(O=),2-R1,3-(R-CO-),X,CL-3,4-DIHYDRO-2H-1,2BENZOISOTHIAZOLE BENZOTHIAZINE IN WHICH: X IS SELECTED FROM THE CLASS CONSISTING OF HYDROGEN AND THE SULFAMOYL GROUP; R IS SELECTED FROM THE CLASS CONSISTING OF ALKYL HAVING UP TO 12 CARBON ATOMS, PHENYL-LOWER-ALKYL, PHENYL, BIPHENYL, PHENYL SUBSTITUTED BY HALOGEN HAVING A MAXIMUM ATOMIC WEIGHT OF 80, PHENYL SUBSTITUTED BY A MAXIMUM OF TWO ALIPHATIC ETHER FUNCTIONS IN WHICH A MAXIMUM OF 2 CARBON ATOMS ARE INVOLVED, AND CYCLOALKYL AND CYCLOALKYL-ALKYL CONTAINING UP TO 8 CARBON ATOMS; AND R1 IS SELECTED FROM THE CLASS CONSISTING OF HYDROGEN, AND ALKYL, ALKENYL, ALKYNYL, ARALKYL, AND KETO-SUBSTITUED ALKYL AND ARALKYL RADICALS, CONTAINING UP TO 9 CARBON ATOMS. 